David Fernandez-AntoranGroup leader
Radiation biology and cell competition
Healthy adult epithelial tissues progressively accumulate clones of cells carrying mutations implicated in cancer and their expansion follows Darwinian evolution rules. Some mutations can increase cell fitness and promote the growth of clones at the expenses of the non-mutated normal adjacent cells, in a process of clonal competition.
Ionising radiation has long been studied as one of the most common environmental mutagenic agents that promotes tumour formation by damaging DNA and creating new oncogenic mutations. However, little is known about its effects on cell competition, clonal evolution and tissue dynamics.
We have recently shown that it can act as a selective pressure, affecting cell competition mechanisms and promoting selection of pre-existing oncogenic mutations, which might affect field cancerisation and increase the risk of cancer development in the future.
We use long-term human and mouse 3D primary epithelial cultures, in vivo cell lineage tracing, mathematical modelling, next generation sequencing methods and state-of-the-art confocal microscopy techniques to unravel the molecular responses and the cellular interactions that control normal and mutant cell behaviours after exposure to different doses of ionising radiation.
The final aim of our research is to understand the effects of ionising radiation in tumours and normal tissues and set the basis for designing external interventions that can modulate cell competition outcomes, eliminate oncogenic mutations from tissues and reduce the risk of cancer initiation and progression.
Colom B et al. (2021) Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature 598: 510–514. DOI: 10.1038/s41586-021-03965-7.
Fowler JC et al. (2021) Selection of Oncogenic Mutant Clones in Normal Human Skin Varies with Body Site. Cancer Discovery DOI: 10.1158/2159-8290.CD-20-1092.
Piedrafita G et al. (2020) A single-progenitor model as the unifying paradigm of epidermal and esophageal epithelial maintenance in mice. Nature Communications 11: 1429. DOI: 10.1038/s41467-020-15258-0.
Fernandez-Antoran D et al. (2019) Outcompeting p53-mutant cells in the normal esophagus by redox manipulation. Cell Stem Cell 25: P329-341.E6. DOI: 10.1016/j.stem.2019.06.011.
Martincorena I et al. (2018) Somatic mutant clones colonize the human esophagus with age. Science 362: 911-917. DOI: 10.1126/science.aau3879
David Fernandez-Antoran PhD, CRUK-RadNet Group Leader, Member of the University Department of Pathology
I did my PhD in Immunology at the Spanish National Centre for Biotechnology (CNB-Madrid), where I studied the role of the proto-oncogene c-myc and its partner max in the development and maturation of B-lymphocytes in vivo.
In 2013 I started a postdoctoral position in the laboratory of Prof. Philip H. Jones (MRC-Cancer Unit / University of Cambridge and The Sanger Institute), funded by European Radiation Agency, where I developed a profound knowledge of epithelial tissue architecture, cell behaviour, radiation biology and cancer development. I studied how epithelial progenitor cells respond to environmental factors like low doses of ionising radiation and how this affects clonal competition within healthy tissues. I demonstrated that these exposures promote the expansion of oncogenic mutations in the oesophageal epithelium. I also demonstrated for the first time how to interfere with this process and deplete mutant cells by manipulating redox status, which opens a new field of study for future interventions in humans in order to reduce cancer risk.
In collaboration with colleagues from The Sanger and Wellcome Stem Cell Institutes, I developed and optimized a new model of in vitro long-term and self-maintaining 3D primary culture using mouse and human epithelial tissues. This system affords a novel concept in the field and allows long-term studies on tissue regeneration, cell-to-cell dynamic interactions, drug responses as well as monitoring early steps of tumour development in vitro.
I started my own laboratory, funded by CRUK-RadNet, at The Gurdon Institute in 2020. Our aim is to understand how radiotherapy treatments (among others environmental factors), modulate cell competition mechanisms in different epithelia, by introducing new selective pressures that change the mutational landscape and might affect tissue function and promote carcinogenesis.
Notable achievements and honours
2021Isaac Newton Trust / Wellcome Trust ISSF / University of Cambridge Joint Research Grants Scheme
2013RISK – IR GRANT. FP7-EURATOM-FISSION
Research Assistant/ Lab Manager
Dr Jose Valverde Lopez